GOAL: SYSTEMATIC REVIEW OF CLINICAL COMPLICATIONS OF SICKLE CELL TRAIT (SCT) For Aim 1: A systematic review of published original research articles between January 1970 and June 30, 2018 that reported an association between SCT and clinical outcomes of interest were reviewed by an expert working group. We followed standard procedures for systematic reviews and reported results according to Preferred Reporting Items for Systematic Reviews (PRISMA) guidelines. The study excluded: 1) non-English language research articles; 2) research articles that reported exclusively on patients with sickle cell disease, in vitro cells, or nonhuman animals; 3) research articles that solely examined physiological mechanisms, laboratory parameters, or had no information on clinical outcomes; 4) prevalence studies, case reports, case series, meeting abstracts, editorials and commentaries; and 5) systematic reviews and review articles after their bibliographies had been reviewed for previously unidentified articles.) Of 7,083 screened studies, 41 met inclusion criteria. There was strong evidence for a positive association between SCT and risk for pulmonary embolism, proteinuria, and chronic kidney disease. There was moderately strong evidence for a positive association between SCT and exertional rhabdomyolysis and for a null association between SCT and deep venous thrombosis, heart failure/cardiomyopathy, stroke, and pediatric height/weight. Absolute risks for the thromboembolism and rhabdomyolysis complications were small. There were either insufficient data or low strength of evidence regarding associations for the remaining 15 clinical outcomes reported in these studies. See Naik RP. et al., Clinical Outcomes Associated With Sickle Cell Trait, Annals of Internal Medicine. 169, 619 (2018). GOAL: EXPLORING THE GENOMIC AND ENVIRONMENTAL CONTRIBUTIONS TO SICKLE CELL DISEASE AND LEG ULCERS Aim 2: The study of leg ulcers in sickle cell disease is ongoing. As of September 1, 2019, we have recruited 235 participants. We have increased our accrual goal for the skin microbiome study up to 250 participants. We will recruit and sample participants with active ulcers, currently with a healed leg ulcer, and those with no previous history of leg ulcers. Additionally, we will compare a previously published microbiome dataset from diabetic foot ulcers to SCD leg ulcers to identify microbial signatures (similarities or differences) that exist in the microbial communities present in the different ulcers, which may be important in the healing process. Aim 3: We will conduct a cross-sectional study to investigate, resilience, stress, social function, health behaviors, and quality of life indicators for each participant with the goal of identifying environmental (i.e. social, physical, and psychosocial) factors that may impact sickle cell disease and the formation and healing of leg ulcers. Aim 4: We will conduct genomic sequencing to seek to identify the role of genetic modifiers in patients with and without leg ulcers. Specifically, we will conduct whole genome sequencing in the participants to study the genetic factors responsible for variation in leg ulceration in our patient population. Aim 5: We will develop and evaluate a return of genomic results program for INSIGHTS study participants. We will conduct an ethnographic study to collect longitudinal data to examine study participants that receive genomics results and assess health behaviors and treatment decisions over time. We predict that the population of study participants that are most in need of support in addressing unexpected genomic results will be low-income and under-insured individuals.